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A potential first-in-class investigational microbiome therapeutic, SER-109, was safe and observed to sustain low Clostridioides difficile (C. diff) recurrence rates for adults, according to the phase III, single-arm ECOSPOR IV study.

Recurrence of C. diff infections occurred in 8.7% of patients at week 8 after receiving a short course of capsules containing purified Firmicutes bacteria spores, according to Sahil Khanna, MBBS, of the Mayo Clinic in Rochester, Minnesota.

And recurrence rates were just as low for those who suffered two or more recurrent C. diff episodes as for those with only one prior infection by week 8 (9.7% vs 6.5%), Khanna reported in a presentation at the American College of Gastroenterology annual meeting.

By 8 weeks, 52% of participants had treatment-emergent adverse events, but most were mild or moderate in severity and gastrointestinal in nature. While 8% experienced serious treatment-emergent adverse events and six of the 263 died through 8 weeks, neither were deemed related to the treatment. Two other patients died over an extended follow-up period, but these were also deemed unrelated to SER-109.

"This is another example of where you could potentially use a live biotherapeutic for your patients with C. difficile infection earlier in the course of the infection after two or more episodes, different from FMT [fecal microbiota transplant] where we think about FMT for three or more episodes of C. difficile infection," Khanna concluded.

When looking at prior antibiotics, no significant difference in C. diff recurrences were seen among the 73% who had received vancomycin and the rest who had gotten prior fidaxomicin (8.9% vs 8.3%).

Reached for comment, Brian B. Baggott, MD, whose group at the Cleveland Clinic participated in a prior trial with the therapeutic, said the study "adds to the evolving efficacy and safety profile for SER-109."

"Microbiome therapeutics are an exciting area that seek to restore the damaged microbiome after antibiotic exposure," Baggott told MedPage Today. "SER-109 is live purified Firmicutes bacterial spores that compete for essential gut biome nutrients, with the net effect of modulating bile acid profiles."

"This augmentation of secondary bile acids in the gut lumen inhibits the C. diff spore germination that leads to recurrent C. diff infection," explained Baggott.

Khanna pointed to the irony of antibiotics' use in C. diff: "Antibiotics cause C. difficile infection, we all know that. Antibiotics disrupt the gut microbiome; the vegetable form of C. difficile-produced toxin leads to disease such as pseudomembranous colitis; and then we end up treating this disease again with antibiotics, which are ineffective in eradicating C. difficile because they are only active against the vegetative forms -- not active against the spores -- and also active against the rest of the gut microbiome."

Bacteria form tough oval or spherical spore structures to protect against unfavorable environmental conditions, including extreme temperatures, radiation, desiccation, and chemical agents.

"We really need to repair the gut microbiome, because the resilient, diverse gut microbiome is active against C. difficile spores and can break the cycle of recurrence. That's where fecal transplant and these live biotherapeutics that are in clinical development come into play," he said. "If you have to repair the microbiome, you gotta do it early in the course when you stop antibiotics."

In the prior randomized ECOSPOR III trial, SER-109 was shown superior to placebo in reducing the risk of C. diff recurrence at 8 weeks, with a sustained clinical response, among those who suffered at least three recurrences. Extended follow-up showed a continued benefit with SER-109 at 24 weeks, where half as many experienced C. diff recurrence versus placebo.

Beyond donor screening, manufacturing processes of SER-109 are designed to inactivate vegetative parasites, bacteria, fungi, and viruses to mitigate any risk to patients.

For the ECOSPOR IV study, Khanna and colleagues examined data on 263 patients with recurrent C. diff who received four capsules once per day of SER-109 for 3 days after being treated with standard of care antibiotics across 72 centers in the U.S. and Canada. In this open-label study, patients were stratified into two cohorts: 29 patients rolled over from ECOSPOR III after being diagnosed by the toxin enzyme immunoassay (EIA) test and 234 patients who had at least one C. diff recurrence and were diagnosed by toxin EIA or polymerase chain reaction (PCR). One day prior to dosing, all received 10 oz of magnesium citrate, used in bowel preparation.

Mean age was 64 (about half were over 65 at baseline), 68% of participants were women, and nearly all were white. Some 71% had experienced at least two recurrences of C. diff. Most patients had multiple comorbidities, including 31% with cardiac disorders, 21% with neoplasms, and 11% with type II diabetes. Overall Charlson comorbidity index was 3.8 after adjusting for mean age.

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